Affinage

ALOX5

Polyunsaturated fatty acid 5-lipoxygenase · UniProt P09917

Length
674 aa
Mass
78.0 kDa
Annotated
2026-06-09
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALOX5 encodes arachidonate 5-lipoxygenase, the enzyme that oxygenates arachidonic acid to 5(S)-HpETE and downstream 5-HETE and leukotrienes (LTB4, LTC4), and through these lipid mediators it acts as a central regulator of inflammatory cell behavior, regulated cell death, and tumor biology (PMID:31664810, PMID:17484769). Catalytic specificity for 5(S)-lipoxygenation and leukotriene synthase activity is set by a small set of 'triad determinant' active-site residues (F359/A424/N425/A603); mutating these shifts the enzyme toward 15(S)- and 8(S)-HpETE production, abolishes leukotriene synthesis, and broadens substrate acceptance, a specificity logic conserved in the zebrafish ortholog (PMID:31664810, PMID:26456699). Enzymatic output bifurcates into two functional arms: a leukotriene arm in which LTB4 drives downstream signaling — activating NF-κB in hepatoma cells, driving Ca2+ influx through ORAI3 to license NLRP3 inflammasome-mediated pyroptosis in CD4+ T cells, and recruiting BLT-receptor-bearing M2 macrophages — and a lipid-peroxidation arm in which ALOX5 executes ferroptosis (PMID:22293202, PMID:38412254, PMID:38124204, PMID:38062004). ALOX5-driven ferroptosis depends on its essential cofactor FLAP, whose stabilization (including by mutant huntingtin) enhances lipoxygenase activity and lipid peroxidation, and on ERK-dependent phosphorylation that targets ALOX5 to the nuclear membrane, where it can drive caspase-independent death; this peroxidation activity also engages autophagy/AMPK-mTOR signaling and GPX4 suppression (PMID:36921996, PMID:36231015, PMID:37080437). Activity is gated by translocation from cytoplasm to nuclear membrane upon cell activation (PMID:17484769, PMID:11016533), and the enzyme is controlled both transcriptionally — its GC-rich, G-quadruplex-forming promoter is bound by Sp1/Sp3-family and other zinc-finger factors, by EGR1, and by PRC2-mediated repression — and post-translationally by FLAP stabilization, PARP-1 PARylation, and inhibitory binding by PEDF-R/PNPLA2 (PMID:32096311, PMID:38062004, PMID:28500307, PMID:38172525, PMID:27635633). Functionally, ALOX5 is required for BCR-ABL leukemia stem cell maintenance, contributes to TKI resistance and chemoresistance across leukemia and solid tumors, supports tumor-associated macrophage polarization and invasion, and modulates beta-cell insulin secretion, osteoclastogenesis, ischemic injury, and stress-induced tau pathology (PMID:19503090, PMID:33561320, PMID:18421434, PMID:22128029, PMID:25122659, PMID:20011686, PMID:37348233).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2000 Medium

    Established that 5-LOX is dynamically regulated at the level of subcellular distribution, with activation reflected by increased membrane-associated enzyme — framing translocation as a control point for activity.

    Evidence RT-PCR, Western blot, and membrane/cytosol fractionation in aging rat brain

    PMID:11016533

    Open questions at the time
    • Does not define the molecular trigger for translocation
    • Correlative with aging, not causal for any phenotype
  2. 2008 High

    Showed ALOX5 has a physiological role beyond inflammation, supporting glucose-stimulated insulin secretion and beta-cell gene expression, indicating broad tissue functions.

    Evidence Alox5-/- mice and siRNA knockdown in human islets with insulin secretion and PDX1/insulin expression readouts

    PMID:18421434

    Open questions at the time
    • Lipid-mediator effector linking ALOX5 to insulin transcription not identified
    • Mechanism connecting enzyme activity to PDX1 regulation unknown
  3. 2009 High

    Defined ALOX5 as a non-redundant requirement for leukemia stem cell function, establishing it as a selective therapeutic vulnerability in BCR-ABL CML.

    Evidence Alox5-/- mice with BCR-ABL transduction, bone marrow transplantation, and LSC functional assays plus zileuton

    PMID:19503090

    Open questions at the time
    • The downstream lipid mediator driving LSC maintenance not pinpointed
    • Why normal HSCs are spared mechanistically unresolved
  4. 2009 High

    Demonstrated chemically how 5-LOX products converge with COX-2 to generate classic lipid peroxidation aldehydes, linking the enzyme to oxidative damage chemistry.

    Evidence In vitro enzymatic reactions with heme/iron treatment and chiral HPLC product characterization

    PMID:19553698

    Open questions at the time
    • Cellular relevance of the di-endoperoxide pathway not demonstrated
    • Does not test contribution to disease phenotypes
  5. 2007 Medium

    Linked ALOX5 localization state to functional leukotriene output in T cells, showing activation-dependent nuclear translocation and stimulus-gated leukotriene synthesis.

    Evidence Western blot, immunofluorescence, and leukotriene synthesis assays with inhibitors in T lymphocytes and Jurkat cells

    PMID:17484769

    Open questions at the time
    • Signal driving translocation not defined
    • Requirement for exogenous arachidonate leaves endogenous substrate supply open
  6. 2012 Medium

    Connected ALOX5 enzymatic output to transcriptional signaling by showing LTB4 activates NF-κB, providing a route from lipid mediator to gene expression.

    Evidence siRNA knockdown, MK886 inhibition, and NF-κB reporter/Western assays with exogenous LTB4 in hepatoma cells

    PMID:22293202

    Open questions at the time
    • LTB4 receptor mediating NF-κB activation not identified here
    • Single cell-type context
  7. 2013 High

    Placed ALOX5 within an upstream signaling cascade for inflammatory migration, identifying it as a c-Jun transcriptional target repressed by CB2 signaling.

    Evidence Chemical genetic screen and zinc-finger nuclease mutagenesis in zebrafish plus human myeloid migration assays

    PMID:23539630

    Open questions at the time
    • Direct binding of c-Jun to the ALOX5 promoter not shown
    • Lipid mediator executing migration not specified
  8. 2017 Medium

    Identified opposing transcriptional control of ALOX5 in leukemia, with PRC2 silencing the gene and its restoration sensitizing cells to chemotherapy.

    Evidence Microarray, PRC2 ChIP, colony assays, and in vivo AML chemotherapy model

    PMID:28500307

    Open questions at the time
    • Mechanism by which restored ALOX5 sensitizes to drugs not established
    • Relationship to its LSC-promoting role left unreconciled
  9. 2019 High

    Mapped the structural basis of 5-LOX reaction specificity to discrete triad-determinant residues, defining how positional and stereo selectivity and leukotriene synthase activity are encoded.

    Evidence Site-directed mutagenesis, Sf9 expression, chiral HPLC, kinetics, and QM/MM simulations on human ALOX5; corroborated in the zebrafish ortholog

    PMID:26456699 PMID:31664810

    Open questions at the time
    • In vitro specificity not tied to a cellular phenotype
    • FLAP dependence not addressed in the reconstituted system
  10. 2020 Medium

    Resolved the cis- and trans-elements controlling ALOX5 transcription, cataloguing promoter-binding zinc-finger factors and confirming a regulatory G-quadruplex; also defined receptor-driven (LPS/TGF-β) promoter activation.

    Evidence DNA pulldown mass spectrometry, G-quadruplex spectroscopy/antibody detection, and promoter-luciferase/product assays in monocytic cells

    PMID:32096311 PMID:32120263

    Open questions at the time
    • Functional contribution of individual zinc-finger factors not dissected
    • Role of the G-quadruplex in cellular ALOX5 regulation not tested
  11. 2022 High

    Defined the activation logic of ALOX5-driven ferroptosis, showing ERK-dependent phosphorylation targets the enzyme to the nuclear membrane to execute caspase-independent death, with LysOX/ERK as an upstream driver.

    Evidence Genome-wide siRNA screen, caspase-9/Alox5 double-KO mice, localization and lipid peroxidation assays; AAV LysOX overexpression and BAPN inhibition in a seizure model

    PMID:36176900 PMID:36231015

    Open questions at the time
    • Identity of the ERK isoform phosphosite on ALOX5 not fully mapped
    • How nuclear-membrane localization generates cytolytic lipid species unresolved
  12. 2023 High

    Established FLAP stabilization as the rate-limiting determinant of ALOX5-mediated, ACSL4-independent ferroptosis and showed mutant huntingtin hijacks this axis in neurodegeneration.

    Evidence RNAi screen, CRISPR knockout, overexpression, and in vivo HD mouse lifespan analysis

    PMID:36921996

    Open questions at the time
    • Molecular mechanism of FLAP stabilization by mHTT not defined
    • Generality across other ferroptosis settings untested
  13. 2023 Medium

    Extended ALOX5 ferroptosis control to additional effector branches, linking it to autophagy-dependent ferroptosis via AMPK/mTOR and GPX4 suppression in melanoma.

    Evidence qRT-PCR, Western blot, iron/GSH/MDA assays, autophagy inhibition, and xenograft with recombinant ALOX5

    PMID:37080437

    Open questions at the time
    • Direct mechanism connecting ALOX5 to AMPK/mTOR not established
    • Whether GPX4 suppression is cause or consequence unclear
  14. 2024 High

    Delineated a complete LTB4 effector cascade in autoimmune inflammation: ALOX5→LTB4→ORAI3 Ca2+ influx→NLRP3→pyroptosis in CD4+ T cells, providing a defined disease-relevant signaling axis.

    Evidence siRNA knockdown, pharmacological inhibition, Ca2+ flux and NLRP3 assays, and rodent RA models

    PMID:38412254

    Open questions at the time
    • LTB4 receptor coupling to ORAI3 not molecularly resolved
    • Contribution relative to other inflammatory pathways in RA not quantified
  15. 2024 Medium

    Identified post-translational stabilization of ALOX5 by PARP-1 PARylation, defining a non-transcriptional route to elevated enzyme levels in pro-metastatic neutrophils.

    Evidence IP/MS, Co-IP, knockdown, in vitro invasion assays, and an in vivo tumor model

    PMID:38172525

    Open questions at the time
    • PARylation sites on ALOX5 not mapped
    • Reciprocal validation of the interaction limited to single lab
  16. 2024 Medium

    Showed ALOX5-derived 5-HETE reprograms tumor-associated myeloid cells toward immunosuppressive M2/PD-L1 states via NRF2 nuclear translocation, broadening its tumor-microenvironment role.

    Evidence UHPLC-MS/MS oxylipin profiling, orthotopic glioma model, flow cytometry, and an ALOX5-targeting nanobody

    PMID:39142719

    Open questions at the time
    • How 5-HETE triggers NRF2 translocation mechanistically unknown
    • Receptor mediating 5-HETE efflux/uptake not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single enzyme is partitioned between its pro-survival leukotriene-signaling outputs and its pro-death lipid-peroxidation/ferroptosis outputs within and across cell types, and what governs that switch.
  • No unified model linking localization, FLAP availability, and product identity to outcome
  • Determinants selecting LTB4 versus lipid-peroxidation fate uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0008289 lipid binding 2 GO:0140098 catalytic activity, acting on RNA 2 GO:0016829 lyase activity 1
Localization
GO:0005635 nuclear envelope 3 GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3
Partners
ALOX5APPARP1PNPLA2

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Loss of Alox5 gene prevents BCR-ABL-induced chronic myeloid leukemia in mice by impairing leukemia stem cell (LSC) function—affecting differentiation, cell division, and survival of long-term LSCs—without significantly affecting normal hematopoietic stem cells. Genetic knockout (Alox5-/- mice), BCR-ABL retroviral transduction, bone marrow transplantation, LSC functional assays Nature genetics High 19503090
2023 ALOX5 mediates ACSL4-independent ferroptosis in Huntington's disease by stabilizing FLAP (its essential cofactor), thereby enhancing ALOX5-mediated lipoxygenase activity and lipid peroxidation in neurons; mHTT (HTTQ94) activates this pathway by stabilizing FLAP. RNAi screening, CRISPR/Cas9 knockout, overexpression, in vivo HD mouse model with lifespan analysis Genes & development High 36921996
2013 Cannabinoid receptor 2 (Cnr2) suppresses leukocyte inflammatory migration by downregulating Alox5 expression via inhibition of the JNK/c-Jun signaling pathway; alox5 is a transcriptional target of c-Jun, and inactivation of Alox5 blocks leukocyte migration. Chemical genetic screen in zebrafish, zinc finger nuclease-mediated mutagenesis of Cnr2, zebrafish leukocyte migration assay, human myeloid cell migration assays The Journal of biological chemistry High 23539630
2022 ERK1-dependent phosphorylation of Alox5 is critical for targeting Alox5 to the nuclear membrane to mediate lipid peroxidation, resulting in nuclear translocation of cytolytic molecules and caspase-9-independent cell death; double knockout of caspase-9 and Alox5 in mice leads to significant T cell expansion, demonstrating these pathways act in parallel. Genome-wide siRNA library screening, double-knockout mice (caspase-9/Alox5), subcellular localization studies, lipid peroxidation assays Cells High 36231015
2019 Mutagenesis of 'triad determinant' residues (F359W/A424I/N425M/A603I) in human ALOX5 shifts reaction specificity from dominant 5(S)-HpETE production to 15(S)- and 8(S)-HpETE, abolishes leukotriene synthase activity, broadens substrate acceptance to C18 fatty acids, and alters substrate orientation at the active site as confirmed by QM/MM calculations. Site-directed mutagenesis, Sf9 insect cell expression, product analysis by chiral HPLC, kinetic studies with deutero-labeled substrates, molecular dynamics and QM/MM simulations ACS chemical biology High 31664810
2015 Zebrafish ALOX2 (functional ortholog of human ALOX5) is an arachidonic acid 5S-lipoxygenating enzyme with leukotriene synthase activity; mutagenesis of its triad determinants (F359W/A424I/N425M) shifts specificity from 5S- to dominant 15S-lipoxygenation, analogous to human ALOX5. Cloning and expression in pro- and eukaryotic systems, product characterization, site-directed mutagenesis Biochimica et biophysica acta High 26456699
2009 Oxygenation of the 5-lipoxygenase product 5S-HETE by COX-2 yields a bicyclic di-endoperoxide; heme-catalyzed cleavage of this di-endoperoxide produces 4S-HNE, 8-oxo-5S-hydroxy-6E-octenoic acid, and malondialdehyde, establishing a convergent 5-LOX/COX-2 pathway to classic lipid peroxidation products. In vitro enzymatic reactions, hematin/ferrous iron treatment, chiral HPLC analysis of products Journal of lipid research High 19553698
2022 LysOX (lysyl oxidase) promotes ALOX5-mediated ferroptotic lipid peroxidation in neurons via activation of ERK signaling; adeno-associated virus-mediated LysOX overexpression enhances ferroptosis sensitivity and aggravates seizure-induced hippocampal damage, while LysOX inhibition blocks Alox5 activation and neuronal death. AAV-based gene transfer (overexpression), pharmacological LysOX inhibition (BAPN), seizure mouse model, lipid peroxidation assays Acta pharmaceutica Sinica. B Medium 36176900
2024 ALOX5 increases LTB4 production in RA CD4+ T cells, which stimulates Ca2+ influx through ORAI3 channels, leading to NLRP3 inflammasome activation and pyroptosis; knockdown or pharmacological inhibition of ALOX5 suppresses pyroptosis and improves symptoms in rodent RA models. siRNA knockdown, pharmacological inhibition, Ca2+ flux assays, NLRP3 inflammasome activation assays, rodent RA models Science signaling High 38412254
2021 PKC-β upregulates Alox5 expression via ERK1/2 signaling in CML cells, and Alox5 promotes TKI resistance by inactivating PTEN; this PKC-β/ERK1/2/Alox5/PTEN axis mediates BCR-Abl-independent TKI resistance. shRNA knockdown, gene expression comparison of 84 leukemia-related genes, PTEN activity assays, in vivo CML-PDX mouse model Journal of cellular physiology Medium 33561320
2024 PARP-1 interacts with and PARylates (post-translationally modifies) ALOX5 to stabilize it in cancer-educated neutrophils, leading to increased MMP-9 expression; blocking PARP-1 decreases ALOX5 expression and MMP-9 production, and eliminates neutrophil-mediated lung cancer cell invasion. Immunoprecipitation coupled to mass spectrometry (IP/MS), co-immunoprecipitation (Co-IP), gene knockdown, in vitro invasion assays, in vivo tumor model Cancer biology & medicine Medium 38172525
2020 ALOX5 expression and activity are upregulated by HER2 in breast cancer cells; HER2 inhibition decreases ALOX5 expression and activity but not ALOX5AP expression; ALOX5 mediates breast cancer growth and migration through RhoA, focal adhesion, and PI3K/Akt/mTOR signaling. HER2 inhibitor treatment, siRNA knockdown, proliferation and migration assays, signaling pathway analysis BioMed research international Medium 33224971
2017 ALOX5 is transcriptionally repressed in MLL-rearranged AML via Polycomb repressive complex 2 (PRC2); restoration of Alox5 expression sensitizes leukemic cells to doxorubicin and cytarabine, with this drug-sensitizing effect associated with negative correlation of Stat and K-Ras signaling pathways. Affymetrix microarray profiling, ChIP assays (PRC2), colony-forming/replating assays, bone marrow transplantation, in vivo AML model with chemotherapy Scientific reports Medium 28500307
2008 Alox5 deficiency in mice impairs glucose-stimulated insulin secretion and reduces expression of insulin and Pdx1 genes in islets; siRNA knockdown of ALOX5 in isolated human islets similarly decreases insulin and PDX1 gene expression by ~50% and insulin secretion threefold, demonstrating a direct role of 5-LO in pancreatic beta cell function. Alox5-/- mouse characterization, siRNA knockdown in human islets, glucose tolerance tests, insulin secretion assays Diabetologia High 18421434
2000 In aging rat brain, 5-LOX mRNA and protein increase in hippocampus and cerebellum, and the membrane/cytosol 5-LOX ratio is larger in older rats, indicating increased 5-LOX protein translocation/activation during aging. Quantitative RT-PCR with internal standards, quantitative Western immunoblotting, subcellular fractionation (membrane vs. cytosol) Neurobiology of aging Medium 11016533
2007 5-LOX protein is expressed in peripheral blood T lymphocytes and is present primarily in the cytoplasm with some nuclear localization; it translocates to the nuclear periphery after mitogenic stimulation. Purified resting T lymphocytes cannot synthesize leukotrienes without exogenous arachidonic acid, whereas Jurkat cells produce LTC4 and LTB4 upon CD3-CD28 cross-linking, which is abolished by 5-LOX inhibitors. Western blot, immunofluorescence, FACS, in situ RT-PCR, leukotriene synthesis assays with inhibitors Immunology Medium 17484769
2012 5-LOX and its metabolite LTB4 activate NF-κB in hepatoma cells: inhibition or knockdown of 5-LOX reduces NF-κB p65 mRNA expression, decreases IκBα phosphorylation in the cytoplasm, and reduces nuclear NF-κB p65 levels; exogenous LTB4 activates NF-κB in a dose-dependent manner. siRNA knockdown, MK886 pharmacological inhibition, Western blot, immunofluorescence, transcriptional activity reporter assay Biochemical and biophysical research communications Medium 22293202
2021 ALOX5-derived 5-HETE in gastric cancer cells activates MEK/ERK signaling to promote tumor growth and reduce chemotherapy sensitivity; ALOX5 inhibition suppresses ERK-mediated signaling and enhances chemotherapy efficacy. ALOX5 overexpression and genetic/pharmacological inhibition, ERK pathway analysis by Western blot, growth/survival assays, exogenous 5-HETE addition Cancer medicine Medium 34121352
2024 In glioma, ALOX5-derived 5-HETE promotes M2 polarization, PD-L1 expression, and migration of glioma-associated microglia/macrophages by facilitating nuclear translocation of NRF2; an ALOX5-targeted nanobody suppresses 5-HETE efflux and attenuates M2 polarization. UHPLC-MS/MS oxylipin profiling, orthotopic glioma mouse model, immunofluorescence, flow cytometry, nanobody development, in vivo bioluminescent imaging Journal for immunotherapy of cancer Medium 39142719
2023 In intrahepatic cholangiocarcinoma, LTB4 (metabolite of ALOX5) binds BLT1/BLT2 receptors on tumor-associated macrophages (TAMs) to activate the PI3K pathway, promoting M2 macrophage migration toward tumor cells and ICC progression. In vitro co-culture model, bulk RNA-seq after co-culture, scRNA-seq analysis, xenograft tumor model with ALOX5 inhibitor (zileuton) plus CSF1R inhibitor Journal of translational medicine Medium 38124204
2017 ALOX5 expression in bladder cancer is transcriptionally regulated by EGR1; ALOX5 deficiency (via CRISPR/Cas9) confers resistance to RSL3-induced ferroptosis in high-pathological-stage bladder cancer cells, identifying ALOX5 as a pro-ferroptotic factor downstream of EGR1-mediated transcription. RNA-seq, RNAi loss-of-function, CRISPR/Cas9 knockout, EGR1 transcriptional regulation assays, in vitro and in vivo ferroptosis assays Cell death & disease Medium 38062004
2020 Mass spectrometric DNA pulldown identified 66 specific ALOX5 promoter-binding proteins, including known regulators Sp1 and Sp3, novel zinc finger proteins (KLF13, KLF16, MAZ, PRDM10, VEZF1, ZBTB7A, ZNF281, ZNF579), two helicases (BLM, DHX36), and hnRNPD/hnRNPK; the GC-rich ALOX5 promoter was confirmed to form DNA G-quadruplex structures by spectroscopic and antibody-based methods. DNA pulldown, label-free quantitative mass spectrometry, G-quadruplex spectroscopy, antibody-based detection The FEBS journal Medium 32096311
2020 LPS activates the ALOX5 promoter and synergizes with TGF-β to increase 5-LO mRNA (up to 54-fold in MM1 cells) and protein expression in human monocytic cells, dramatically increasing leukotriene biosynthesis; this represents a receptor-mediated transcriptional control mechanism for 5-LO expression. ALOX5 promoter-luciferase reporter assays, RT-PCR, Western blot, leukotriene product quantification Prostaglandins, leukotrienes, and essential fatty acids Medium 32120263
2011 In Alox5-/- mice on a high-fat diet, enhanced osteoclastogenesis and bone loss occurs with increased RANKL, PPARγ, and COX-2 gene expression in femur; treatment with celecoxib (COX-2 inhibitor) suppresses these increases, placing 5-LO upstream of COX-2-mediated osteoclast activity in a gene-by-environment interaction. Alox5-/- mice on high-fat diet, microarchitectural analysis, histomorphometry, in vitro osteoclastogenesis assay, gene expression, celecoxib rescue Endocrinology Medium 22128029
2014 In 3xTg Alzheimer's disease mice, ALOX5 gene deficiency prevents stress-induced worsening of tau phosphorylation, impaired tau solubility, increased GSK3β activity, compromised long-term potentiation, and fear-conditioned memory deficits caused by restraint/isolation stress. Triple-transgenic 3xTg mice crossed with 5-LO-/- mice, restraint/isolation stress paradigm, tau phosphorylation/solubility assays, GSK3β activity measurement, electrophysiology (LTP), behavioral fear conditioning Human molecular genetics Medium 25122659
2016 PEDF-R (PNPLA2 gene product) physically binds human recombinant 5-LOX via ionic interactions through a specific peptide region (E5b/P1 spanning Leu159–Met325); this binding inhibits 5-LOX lipoxygenase activity and reduces LTB4 levels and RPE cell death during oxidative stress. Peptide-affinity chromatography, pulldown assays with recombinant 5-LOX, lipoxygenase activity assay, LTB4 ELISA, cell viability assays Investigative ophthalmology & visual science Medium 27635633
2009 ALOX5 silencing by RNAi in isolated rat cardiomyocytes reduces ALOX5 expression 4.7-fold, decreases LTC4 levels, and reduces necrotic cell death during anoxia-reoxygenation; in vivo ALOX5 knockdown in rat heart reduces infarct size 3.8-fold during ischemia-reperfusion. siRNA knockdown in cardiomyocytes, real-time PCR, LTC4 measurement, necrosis/viability assays, in vivo rat I/R model Acta biochimica Polonica Medium 20011686
2023 ALOX5 regulates tumor-associated macrophage M2 polarization via the JAK/STAT pathway in pancreatic cancer; ALOX5 overexpression promotes chemotaxis of macrophages toward cancer cells, while zileuton inhibits these effects. Lentiviral ALOX5 overexpression in PANC-1 and macrophages, JAK/STAT pathway analysis, nude mouse orthotopic transplantation model International immunopharmacology Medium 37348233
2023 ALOX5 promotes autophagy-dependent ferroptosis in melanoma by activating the AMPK/mTOR pathway and inhibiting GPX4 expression; inhibition of autophagy reduces ALOX5-enhanced ferroptosis, demonstrating synergy between autophagy and ALOX5 in this cell death pathway. qRT-PCR, Western blot, IHC, iron/GSH/MDA assays, autophagy inhibition, xenograft model with recombinant ALOX5 protein Biochemical pharmacology Medium 37080437
2020 CaMKIIγ knockdown in AML stem-like cell lines downregulates Alox5 levels and decreases c-Myc and p-IκBα (with unchanged total IκBα), placing CaMKIIγ upstream of Alox5 in regulating the Alox5/NF-κB pathway controlling AML stem-like cell viability and self-renewal. shRNA lentiviral knockdown of CaMKIIγ, qRT-PCR, Western blot for NF-κB pathway components, CD34+ cell proportion analysis International journal of laboratory hematology Low 33369192

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature genetics 394 10369259
2009 Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nature genetics 249 19503090
2005 Dual inhibition of 5-LOX and COX-2 suppresses colon cancer formation promoted by cigarette smoke. Carcinogenesis 130 15637091
2018 Safer anti-inflammatory therapy through dual COX-2/5-LOX inhibitors: A structure-based approach. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 117 29883727
2021 A novel mechanism linking ferroptosis and endoplasmic reticulum stress via the circPtpn14/miR-351-5p/5-LOX signaling in melatonin-mediated treatment of traumatic brain injury. Free radical biology & medicine 93 34883251
2023 ALOX5-mediated ferroptosis acts as a distinct cell death pathway upon oxidative stress in Huntington's disease. Genes & development 91 36921996
2011 Psoralidin, a dual inhibitor of COX-2 and 5-LOX, regulates ionizing radiation (IR)-induced pulmonary inflammation. Biochemical pharmacology 79 21669192
2008 ALOX5 variants associated with susceptibility to human pulmonary tuberculosis. Human molecular genetics 77 18174194
2018 Frontline Science: Reprogramming COX-2, 5-LOX, and CYP4A-mediated arachidonic acid metabolism in macrophages by salidroside alleviates gouty arthritis. Journal of leukocyte biology 58 30265377
2023 The ALOX5 inhibitor Zileuton regulates tumor-associated macrophage M2 polarization by JAK/STAT and inhibits pancreatic cancer invasion and metastasis. International immunopharmacology 57 37348233
2013 Cannabinoid receptor 2 suppresses leukocyte inflammatory migration by modulating the JNK/c-Jun/Alox5 pathway. The Journal of biological chemistry 56 23539630
2018 Inhibition of COX-2/mPGES-1 and 5-LOX in macrophages by leonurine ameliorates monosodium urate crystal-induced inflammation. Toxicology and applied pharmacology 55 29763636
2017 MiR-216a-3p inhibits colorectal cancer cell proliferation through direct targeting COX-2 and ALOX5. Journal of cellular biochemistry 55 28786533
2023 ALOX5 promotes autophagy-dependent ferroptosis by activating the AMPK/mTOR pathway in melanoma. Biochemical pharmacology 54 37080437
2006 ALOX5 promoter genotype, asthma severity and LTC production by eosinophils. Allergy 54 16364163
2016 5-LOX Inhibitor Zileuton Reduces Inflammatory Reaction and Ischemic Brain Damage Through the Activation of PI3K/Akt Signaling Pathway. Neurochemical research 53 27380038
2023 ALOX5 deficiency contributes to bladder cancer progression by mediating ferroptosis escape. Cell death & disease 51 38062004
2008 ALOX5 promoter genotype and response to montelukast in moderate persistent asthma. Respiratory medicine 51 18339529
2018 mPGES-1 and ALOX5/-15 in tumor-associated macrophages. Cancer metastasis reviews 50 29808459
2009 The Alox5 gene is a novel therapeutic target in cancer stem cells of chronic myeloid leukemia. Cell cycle (Georgetown, Tex.) 50 19823023
2008 Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease. Human genetics 48 18369664
2008 Identification of ALOX5 as a gene regulating adiposity and pancreatic function. Diabetologia 48 18421434
2000 Inflammatory 5-LOX mRNA and protein are increased in brain of aging rats. Neurobiology of aging 47 11016533
2024 Elucidating the role of tumor-associated ALOX5+ mast cells with transformative function in cervical cancer progression via single-cell RNA sequencing. Frontiers in immunology 46 39224598
2003 Promoter polymorphism in the 5-lipoxygenase (ALOX5) and 5-lipoxygenase-activating protein (ALOX5AP) genes and asthma susceptibility in a Caucasian population. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 46 12911785
2022 Design, synthesis, and molecular docking of novel pyrazole-chalcone analogs of lonazolac as 5-LOX, iNOS and tubulin polymerization inhibitors with potential anticancer and anti-inflammatory activities. Bioorganic chemistry 45 36166898
2015 Dual inhibition of COX-2/5-LOX blocks colon cancer proliferation, migration and invasion in vitro. Oncology reports 45 26707712
2017 Effects of COX1-2/5-LOX blockade in Alzheimer transgenic 3xTg-AD mice. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 44 28238167
2007 COX-2/5-LOX dual acting anti-inflammatory drugs in cancer chemotherapy. Current topics in medicinal chemistry 42 17305571
2015 The 5-lipoxygenase (5-LOX) Inhibitor Zileuton Reduces Inflammation and Infarct Size with Improvement in Neurological Outcome Following Cerebral Ischemia. Current neurovascular research 41 26265153
2017 Synthesis of novel hybrids of pyrazole and coumarin as dual inhibitors of COX-2 and 5-LOX. Bioorganic & medicinal chemistry letters 40 28720504
2021 Synthetically-tailored and nature-derived dual COX-2/5-LOX inhibitors: Structural aspects and SAR. European journal of medicinal chemistry 39 34479036
2018 Inhibition of COX-2 and 5-LOX regulates the progression of colorectal cancer by promoting PTEN and suppressing PI3K/AKT pathway. Biochemical and biophysical research communications 39 29339153
2022 Critical involvement of lysyl oxidase in seizure-induced neuronal damage through ERK-Alox5-dependent ferroptosis and its therapeutic implications. Acta pharmaceutica Sinica. B 38 36176900
2005 5-Lipoxygenase (ALOX5) and FLAP (ALOX5AP) gene polymorphisms as factors in vascular pathology and Alzheimer's disease. Medical hypotheses 36 16278051
2021 ALOX5-5-HETE promotes gastric cancer growth and alleviates chemotherapy toxicity via MEK/ERK activation. Cancer medicine 35 34121352
2017 ALOX5 exhibits anti-tumor and drug-sensitizing effects in MLL-rearranged leukemia. Scientific reports 35 28500307
2015 Indole based peptidomimetics as anti-inflammatory and anti-hyperalgesic agents: Dual inhibition of 5-LOX and COX-2 enzymes. European journal of medicinal chemistry 35 25956953
2014 Absence of ALOX5 gene prevents stress-induced memory deficits, synaptic dysfunction and tauopathy in a mouse model of Alzheimer's disease. Human molecular genetics 34 25122659
2015 Simultaneous targeting of 5-LOX-COX and EGFR blocks progression of pancreatic ductal adenocarcinoma. Oncotarget 33 26429877
2021 Baicalin and Geniposide Inhibit Polarization and Inflammatory Injury of OGD/R-Treated Microglia by Suppressing the 5-LOX/LTB4 Pathway. Neurochemical research 31 33891262
2020 Identification and development of thiazole leads as COX-2/5-LOX inhibitors through in-vitro and in-vivo biological evaluation for anti-inflammatory activity. Bioorganic chemistry 31 32361295
2013 ALOX5 polymorphism associates with increased leukotriene production and reduced lung function and asthma control in children with poorly controlled asthma. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 31 23600541
2024 ALOX5 drives the pyroptosis of CD4+ T cells and tissue inflammation in rheumatoid arthritis. Science signaling 30 38412254
2021 Licofelone, a potent COX/5-LOX inhibitor and a novel option for treatment of neurological disorders. Prostaglandins & other lipid mediators 30 34517113
2011 ALOX5 gene variants affect eicosanoid production and response to fish oil supplementation. Journal of lipid research 30 21296957
2007 Inhibitory activities and attenuated expressions of 5-LOX with red ginseng in Helicobacter pylori-infected gastric epithelial cells. Digestive diseases and sciences 30 17333352
2020 Conjugated linoleic acid attenuates 2,4-dinitrofluorobenzene-induced atopic dermatitis in mice through dual inhibition of COX-2/5-LOX and TLR4/NF-κB signaling. The Journal of nutritional biochemistry 29 32330842
2016 Arachidonate 5-lipoxygenase (ALOX5) gene polymorphism is associated with Alzheimer's disease and body mass index. Journal of the neurological sciences 29 26944113
2016 Serum 5-LOX: a progressive protein marker for breast cancer and new approach for therapeutic target. Carcinogenesis 29 27432812
2012 Lipid metabolism enzyme 5-LOX and its metabolite LTB4 are capable of activating transcription factor NF-κB in hepatoma cells. Biochemical and biophysical research communications 29 22293202
2021 LTB4-Driven Inflammation and Increased Expression of ALOX5/ACE2 During Severe COVID-19 in Individuals With Diabetes. Diabetes 28 34417262
2011 Dual inhibition of 5-LOX and COX-2 suppresses esophageal squamous cell carcinoma. Cancer letters 28 21652147
2009 Convergence of the 5-LOX and COX-2 pathways: heme-catalyzed cleavage of the 5S-HETE-derived di-endoperoxide into aldehyde fragments. Journal of lipid research 28 19553698
2007 Expression of 5-lipoxygenase (5-LOX) in T lymphocytes. Immunology 28 17484769
2016 A Novel Inhibitor of 5-Lipoxygenase (5-LOX) Prevents Oxidative Stress-Induced Cell Death of Retinal Pigment Epithelium (RPE) Cells. Investigative ophthalmology & visual science 27 27635633
2009 Expression and activity of COX-1 and 2 and 5-LOX in joint tissues from dogs with naturally occurring coxofemoral joint osteoarthritis. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 27 19274754
2011 Enhancing antitumor effects in pancreatic cancer cells by combined use of COX-2 and 5-LOX inhibitors. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 26 21993002
2008 Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) selectivity of COX inhibitors. Prostaglandins, leukotrienes, and essential fatty acids 26 18280718
2023 Caffeic acid modulates activation of neutrophils and attenuates sepsis-induced organ injury by inhibiting 5-LOX/LTB4 pathway. International immunopharmacology 25 37913569
2020 Acetyl-11-keto-β-boswellic acid prevents testicular torsion/detorsion injury in rats by modulating 5-LOX/LTB4 and p38-MAPK/JNK/Bax/Caspase-3 pathways. Life sciences 25 32971106
2020 Aberrant ALOX5 Activation Correlates with HER2 Status and Mediates Breast Cancer Biological Activities through Multiple Mechanisms. BioMed research international 25 33224971
2017 Invasive trophoblast promote stromal fibroblast decidualization via Profilin 1 and ALOX5. Scientific reports 25 28821715
2010 Design, synthesis, and biological evaluation of prenylated chalcones as 5-LOX inhibitors. Bioorganic & medicinal chemistry 25 20667741
2023 ALOX5 acts as a key role in regulating the immune microenvironment in intrahepatic cholangiocarcinoma, recruiting tumor-associated macrophages through PI3K pathway. Journal of translational medicine 23 38124204
2023 Novel N-methylsulfonyl-indole derivatives: biological activity and COX-2/5-LOX inhibitory effect with improved gastro protective profile and reduced cardio vascular risks. Journal of enzyme inhibition and medicinal chemistry 21 36458373
2008 5-LOX, 12-LOX and 15-LOX in immature forms of human leukemic blasts. Leukemia research 21 18561999
2005 Licofelone, a novel 5-LOX/COX-inhibitor, attenuates leukocyte rolling and adhesion on endothelium under flow. Biochemical pharmacology 21 15894291
2021 PKC-β/Alox5 axis activation promotes Bcr-Abl-independent TKI-resistance in chronic myeloid leukemia. Journal of cellular physiology 20 33561320
2017 Genetic Variations of Oxidative Stress Related Genes ALOX5, ALOX5AP and MPO Modulate Ischemic Stroke Susceptibility Through Main Effects and Epistatic Interactions in a Chinese Population. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 20 29041000
2015 Variants in ALOX5, ALOX5AP and LTA4H are not associated with atherosclerotic plaque phenotypes: the Athero-Express Genomics Study. Atherosclerosis 20 25721704
2005 Inhibition of COXs and 5-LOX and activation of PPARs by Australian Clematis species (Ranunculaceae). Journal of ethnopharmacology 20 16207522
2024 ALOX5 contributes to glioma progression by promoting 5-HETE-mediated immunosuppressive M2 polarization and PD-L1 expression of glioma-associated microglia/macrophages. Journal for immunotherapy of cancer 19 39142719
2018 5-Lipoxygenase (ALOX5): Genetic susceptibility to type 2 diabetes and vitamin D effects on monocytes. The Journal of steroid biochemistry and molecular biology 19 30521849
2015 The lipoxygenase pathway in zebrafish. Expression and characterization of zebrafish ALOX5 and comparison with its human ortholog. Biochimica et biophysica acta 19 26456699
2024 Quercetin Alleviates LPS-Stimulated Myocardial Injury through Regulating ALOX5/PI3K/AKT Pathway in Sepsis. Cardiovascular toxicology 18 39068603
2017 5-LOX in Alzheimer's Disease: Potential Serum Marker and In Vitro Evidences for Rescue of Neurotoxicity by Its Inhibitor YWCS. Molecular neurobiology 18 28451886
2011 A high-fat diet induces bone loss in mice lacking the Alox5 gene. Endocrinology 18 22128029
2024 Magnolin alleviated DSS-induced colitis by inhibiting ALOX5-mediated ferroptosis. The Kaohsiung journal of medical sciences 17 38340032
2022 Interference of ALOX5 alleviates inflammation and fibrosis in high glucose‑induced renal mesangial cells. Experimental and therapeutic medicine 17 36605525
2021 Discovery of small molecule acting as multitarget inhibitor of colorectal cancer by simultaneous blocking of the key COX-2, 5-LOX and PIM-1 kinase enzymes. Bioorganic chemistry 17 34303896
2016 Copy number variation in ALOX5 and PTGER1 is associated with NSAIDs-induced urticaria and/or angioedema. Pharmacogenetics and genomics 17 26959713
2024 Cancer-educated neutrophils promote lung cancer progression via PARP-1-ALOX5-mediated MMP-9 expression. Cancer biology & medicine 16 38172525
2020 Analysis of proximal ALOX5 promoter binding proteins by quantitative proteomics. The FEBS journal 16 32096311
2020 LPS induces ALOX5 promoter activation and 5-lipoxygenase expression in human monocytic cells. Prostaglandins, leukotrienes, and essential fatty acids 16 32120263
2016 Simultaneous targeting of 5-LOX-COX and ODC block NNK-induced lung adenoma progression to adenocarcinoma in A/J mice. American journal of cancer research 16 27293987
2009 Cardioprotective effect of 5-lipoxygenase gene (ALOX5) silencing in ischemia-reperfusion. Acta biochimica Polonica 16 20011686
2024 Multiomics integrated analysis and experimental validation identify TLR4 and ALOX5 as oxidative stress-related biomarkers in intracranial aneurysms. Journal of neuroinflammation 15 39278904
2007 5-LOX inhibitor modulates the inflammatory responses provoked by Helicobacter pylori infection. Helicobacter 15 17241301
2024 Dual anti-inflammatory activities of COX-2/5-LOX driven by kratom alkaloid extracts in lipopolysaccharide-induced RAW 264.7 cells. Scientific reports 14 39578527
2023 Exosomes derived from human adipose-derived stem cells alleviate hepatic ischemia-reperfusion (I/R) injury through the miR-183/ALOX5 axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 14 36786721
2021 Polyphenolic Profile of Callistemon viminalis Aerial Parts: Antioxidant, Anticancer and In Silico 5-LOX Inhibitory Evaluations. Molecules (Basel, Switzerland) 14 33923148
2020 CaMKIIγ regulates the viability and self-renewal of acute myeloid leukaemia stem-like cells by the Alox5/NF-κB pathway. International journal of laboratory hematology 14 33369192
2019 Mutations of Triad Determinants Changes the Substrate Alignment at the Catalytic Center of Human ALOX5. ACS chemical biology 14 31664810
2015 Exploring the role of chloro and methyl substitutions in 2-phenylthiomethyl-benzoindole derivatives for 5-LOX enzyme inhibition. European journal of medicinal chemistry 14 26708113
2023 Hederagenin protects against myocardial ischemia-reperfusion injury via attenuating ALOX5-mediated ferroptosis. Naunyn-Schmiedeberg's archives of pharmacology 13 37955689
2020 Effects of ALOX5, IL6R and SFTPD gene polymorphisms on the risk of lung cancer: A case-control study in China. International immunopharmacology 13 31918059
2020 Discovery and Development of a Novel mPGES-1/5-LOX Dual Inhibitor LFA-9 for Prevention and Treatment of Chronic Inflammatory Diseases. Journal of inflammation research 13 33408499
2017 Leukotriene signaling via ALOX5 and cysteinyl leukotriene receptor 1 is dispensable for in vitro growth of CD34+CD38- stem and progenitor cells in chronic myeloid leukemia. Biochemical and biophysical research communications 13 28623130
2022 Mitochondrion-Mediated Cell Death through Erk1-Alox5 Independent of Caspase-9 Signaling. Cells 12 36231015

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